Mechanisms by which metals induce cancer are under investigation. Recent work indicates that cadmium can induce tumors of the ventral prostate in rats by various routes of exposure, including oral, and that this is associated with an apparent quiescence of the metallothionein (MT) gene in this specific lobe. As MT is thought to detoxify cadmium, the lack of gene activity in this target tissue may allow more cadmium to interact with critical target molecules. Likewise in the rat testes, another target of cadmium carcinogenesis, the MT gene also does not appear responsive to induction stimuli. Thus, factors may exist in the rat ventral prostate and testes that enhance susceptibility to cadmium. Conversely, transformed liver cells were found to be highly susceptible to cadmium cytotoxicity because of reduced activity of the MT gene. In mice, cadmium inhibits N-nitrosodiethylamine (NDEA)-induced liver and lung tumor formation regardless of route of exposure or sequence of administration and even when lesions are well advanced. Evidence of a deficiency of MT in tumor cells was seen immunohistologically in NDEA-induced liver and lung lesions. Auxiliary studies in a spontaneously transformed liver cell line indicated a marked reduction in basal MT production following transformation. The possibility exists that cadmium has a specific toxicity toward previously initiated cells within liver and lung because the MT gene is only poorly expressed after transformation. Furthermore, in cultured cells expression of MT was a clear factor in reducing cadmium- induced genotoxicity. Thus, tissue specific susceptibility factors play an important role in cadmium carcinogenesis and anticarcinogenesis. This may involve reduced expression of the MT gene. Conversely, selenium prevents cadmium toxicity through a mechanism not involving MT and in spite of markedly enhanced cadmium retention.